St Clair, D.K.;Rybak, S.M.;Riordan, J.F.;Vallee, B.L."Angiogenin abolishes cell-free protein synthesis by specific ribonucleolytic inactivation of ribosomes."Proceedings of the National Academy of Sciences of the United States of America84,23(1987):8330-4.[PubMed Link] | [ Full text ]

The primary research focus of this laboratory is in the area of the mitochondrial antioxidant defense system. We cloned the human gene for the primary superoxide removal enzyme in mitochondria, manganese superoxide dismutase (MnSOD), and the initial study has been expanded into several separate but related projects. These projects involve evaluating genetic abnormalities of antioxidant enzymes, the mechanisms regulating gene expression, and the impact these alterations have on the ability of humans to cope with oxidative stress. We made the seminal observation that expression of MnSOD in mitochondria suppresses neoplastic transformation and promotes differentiation of cancer cells, leading to a reduction in their tumorigenicity and metastatic capability. However, contradictory information in the literature based on random detection of MnSOD in cancer cells and human tissues resulted in confusion as to whether and when MnSOD expression is altered in cancer. To directly address this important question, we generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter/enhancer elements to investigate the changes of MnSOD transcription throughout the development of cancer. The results demonstrate that MnSOD expression was suppressed at a very early stage, but subsequently increased at late stages of skin carcinogenesis. Importantly, the decline in MnSOD expression occurred prior to the development of benign tumors and was concurrent with an increase in glucose utilization. The decline in MnSOD expression in the early stage of cancer was caused by a p53-mediated suppression of MnSOD transcription. However, as the tumor progresses and p53 activity is lost, MnSOD levels rise again, creating conditions in which cancer cells can survive under oxidative stress. The results identify MnSOD as a p53-regulated gene whose expression switches between early and advanced stages of cancer. We further demonstrated that MnSOD serves as a mitochondrial fidelity protein that protects the mitochondrial genome against oxidative stress-induced inactivation. Based on these critical findings, we are testing the hypothesis that defective MnSOD activity signals an adaptive response, leading to activation of a metabolic switch that initiates the Warburg effect, which is an important metabolic change that confers many growth and survival advantages to cancer cells, including a decrease of reactive oxygen species (ROS), a byproduct of mitochondrial energy metabolism.
1. St Clair DK, Wan XS, Oberley TD, Muse KE, St Clair WH: Suppression of radiation-induced neoplastic transformation by overexpression of mitochondrial superoxide dismutase. Mol Carcinog. 6:238-42, 1992.
2. Urano M, Kuroda M, Reynolds R, Oberley TD, St Clair DK: Expression of manganese superoxide dismutase reduces tumor control radiation dose: gene-radiotherapy. Cancer Res. 55:2490-93, 1995.
3. Zhao Y, Xue Y, Oberley TD, Kiningham KK, Lin SM, Yen HC, Majima H, Hines J, St Clair D: Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res. 61:6082-88, 2001.
4. Dhar SK, Tangpong J, Chaiswing L, Oberley TD, and St. Clair DK: Manganese superoxide dismutase is a p53-regulated gene that switches cancers between early and advanced stages. Cancer Res. 71:8864-95, 2011. PMCID: PMC3206134.
5. Xu,Y, Miriyala S, Fang F., Bakthavatchalu V, Noel T, Schell DM, Wang C, St Clair WH, St Clair DK. Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect. Oncogene. 2014 Nov 3. doi: 10.1038/onc.2014.355.

In another research project, our work has led to a paradigm shift in the thinking about the role of antioxidants in cancer therapy. Using MnSOD transgenic and knockout mice, we have demonstrated the important roles of MnSOD in the regulation of cell proliferation and cell death, which, in turn, modulate subsequent tumor formation. The most important outcome from these results is the knowledge that MnSOD inhibits both apoptosis and proliferation induced by ROS-generating carcinogens when given prior to exposure to carcinogens; when MnSOD mimetic is applied after the peak of apoptosis and before the peak of proliferation, the MnSOD mimetic can inhibit ROS-induced proliferation without suppressing ROS-induced apoptosis. The window between apoptosis and proliferation provides an opportunity to utilize an antioxidant intervention that selectively suppresses cell proliferation without interfering with apoptosis. These findings, coupled to our original finding that excessive ROS play an important role in mediating normal tissue injury caused by established chemotherapeutics, reveal a novel strategy that could be exploited for either developing antioxidant-based cancer prevention or sensitizing cancer cells to radiation- or chemo-based therapies.
1. Yen HC, Oberley TD, Vichitbandha S, Ho YS, St Clair DK: The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest. 98:1253-60, 1996.
2. Zhao, Y., Oberley, T.D., Chaiswing, L., Lin, S-M., Epstein, C.J., Huang, T-T., and St. Clair, D.K. Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alteration in AP-1 and p53-mediated pathways in a skin cancer model. Oncogene, 21:3836-846,2002.
3. Zhao Y, Chaiswing L, Velez JM, Batinic-Haberle I, Colburn NH, Oberley TD, St Clair DK: p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. Cancer Res. 65:3745-50, 2005.
4. Zhao Y, Chaiswing L, Velez JM, Batinic-Haberle I, Colburn NH, Oberley TD, St Clair DK: p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. Cancer Res. 65:3745-50, 2005.

Serious long-term therapy-induced impairment among cancer survivors is a currently understudied facet of cancer treatment, but one that is emerging as a critical need given clincial successes with certain cancers and treatment modalities. Our current research direction, based on in-depth understandings from this decades-long focus, into antioxidant defense mechanisms that have intriguing potential to address the challenge of serious post-survival impairment. Our overarching goal is to develop a novel dual-purpose drug approach to be used as a component of combination therapy to 1) improve the efficacy of existing cancer therapeutic protocols and 2) reduce the toxic side effects to normal tissues caused by existing therapeutic strategies. This dual-purpose approach to therapeutics is expected not only to enhance treatment efficacy and thereby increase patient survival but also simultaneously to improve quality of life among cancer survivors.